PROJECT SUMMARY/ABSTRACT Dr. Longbrake is an MD/PhD neuroimmunologist whose long-term goal is to determine the biological mechanisms for inter-individual heterogeneity in multiple sclerosis (MS). The training and mentored research proposed will enable her to develop expertise in statistical methods for microbiome and longitudinal data analysis. This will allow her to build/implement risk prediction models, integrating high-order genetic, metabolomic and immunologic data with patients' clinical disease course to improve medical decision making. Dr. Longbrake has assembled an expert and committed team of mentors and collaborators. Dr. Hafler is a world expert in MS genetics and immunology. Dr. Cotsapas is an bioinformatician with extensive experience integrating genomic and clinical data. Among her advisors, Dr. Xavier and Dr. Palm are authorities on the microbiome in the setting of inflammatory bowel disease and have used genomic and microbiome data to model disease severity. Dr. Waubant is an epidemiologist who pioneered the study of the microbiome in MS and founded several large longitudinal patient cohorts. During her award, Dr. Longbrake will take formal courses at Cold Spring Harbor and Yale, focusing on statistical methods for functional genomics and longitudinal data analysis. She will get hands- on training in microbiome and metabolome data analysis through working with advisors & collaborators. Individuals with MS have widely divergent phenotypes. Some become wheelchair bound within a few years while others have no apparent disability after decades. Moreover, despite the availability of immunomodulatory medications, no biomarkers predict a priori which patients will respond to each treatment. The resultant trial and error leads to morbidity. The gut microbiota are affected by many of the same environmental factors that predispose to MS and play an under-appreciated role in the development of autoimmunity. As an environmentally responsive variable that directly affects the immunophenotype, the gut microbiome is a putative mediator of inter-individual variation in MS severity. We will conduct a longitudinal cohort study of microbiome/immune interactions in MS, enrolling 40 newly diagnosed patients and matched healthy controls for this study. We will compare the gut microbiome, gut metabolome with circulating blood immunophenotypes for untreated patients compared to controls and then evaluate the changes in microbiota and circulating immune cells induced by ocrelizumab, a highly effective, B- cell depleting immunomodulator used to treat MS. This study will help determine whether these factors contribute to inter-individual variability in MS. Upon completion of the mentored award, Dr. Longbrake will be one of the only MS clinician researchers with the training and expertise to juxtapose clinical data with microbiome, metabolome and circulating immunophenotypic data. She will have access to biospecimens and clinical data from a longitudinal cohort of new-onset MS patients, which will become the substrate for future studies, and she will be well positioned to apply for funding as an independent clinician researcher.